Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Viral infection triggers several double-stranded RNA (dsRNA) sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, ribonuclease L (RNase L), that cleaves single-stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here, we show that this fragmentation induces the ribotoxic stress response via ZAKα, potentially through stalled ribosomes and/or ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes. Intriguingly, we found that the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program. [Display omitted] •Activated RNase L acts with dsRNA-sensing pathways to promote cell signaling•RNA fragmentation induces transcription through ZAKα signaling•Activation of RNase L modulates levels of eIF2α phosphorylation•Translation of stress-responsive mRNAs is inhibited by active RNase L Karasik et al. uncovered that widespread mRNA degradation by RNase L leads to changes in gene expression and signaling. In particular, the authors found that RNA fragmentation promotes activation of the ZAKα signaling pathway. The findings establish how mRNA decay can promote innate immunity.